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WO2007009355A1 - Injection de paclitaxel et sa méthode de préparation - Google Patents

Injection de paclitaxel et sa méthode de préparation Download PDF

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Publication number
WO2007009355A1
WO2007009355A1 PCT/CN2006/001665 CN2006001665W WO2007009355A1 WO 2007009355 A1 WO2007009355 A1 WO 2007009355A1 CN 2006001665 W CN2006001665 W CN 2006001665W WO 2007009355 A1 WO2007009355 A1 WO 2007009355A1
Authority
WO
WIPO (PCT)
Prior art keywords
paclitaxel
injection
preparation
stabilizer
solvent
Prior art date
Application number
PCT/CN2006/001665
Other languages
English (en)
Chinese (zh)
Inventor
Jianming Chen
Baoan Gao
Zundong Huang
Haisheng Chen
Qin Xiao
Chengan Huang
Original Assignee
Holley Pharmaceuticals Co. Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Holley Pharmaceuticals Co. Ltd. filed Critical Holley Pharmaceuticals Co. Ltd.
Publication of WO2007009355A1 publication Critical patent/WO2007009355A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid

Definitions

  • the present invention relates to the field of medical technology, and in particular to a novel formulation and a preparation method for preparing a paclitaxel injection by using an injection solvent to dissolve the anticancer drug paclitaxel and using a suitable stabilizer. Background technique
  • Paclitaxel (trade name Taxol) is a potent anticancer drug extracted from Taxus brevidolia (Pacific yew), a complex diterpenoid with a molecular formula of C 47. H 51 N0 14 , relative molecular mass is 853.9. Paclitaxel has good anticancer activity and is effective for treating ovarian cancer, breast cancer, colon cancer, non-small cell lung cancer, cervical cancer, melanoma, and the like.
  • Paclitaxel has a low solubility in water and is almost insoluble in water ( ⁇ 0. 004 mg / ml). Oral administration has poor bioavailability and can only be administered by intravenous injection.
  • the currently used paclitaxel preparation is a mixture of polyoxyethylene castor oil and absolute ethanol 1:1 (Cremophor® EL), which is a paclitaxel Cremophor preparation. When the polyoxyethylene castor oil in the composite solvent is degraded in vivo, It releases histamine, causing a severe allergic reaction.
  • Paclitaxel injection registered in China (trade name is Taxol), the specification states that "to prevent serious allergic reactions, all patients receiving this drug should be given corticosteroids (such as dexamethasone), benzene.
  • corticosteroids such as dexamethasone
  • benzene benzene.
  • Hellamin and H2 receptor antagonists such as cimetidine, ranitidine
  • the administration process requires strict monitoring, the whole process is extremely inconvenient.
  • the Cremophor preparation has poor stability after dilution, and is easy to precipitate, which reduces the safety of clinical medication and affects the absorption and utilization of paclitaxel.
  • cyclodextrin has a large allergic reaction and hemolysis, and large adverse reactions limit the inclusion of paclitaxel cyclodextrin. widely used.
  • Zhang Yuru et al. dissolved paclitaxel, phospholipids and bile salts in an organic solvent and made a powder injection by freeze-drying method.
  • the invention provides a novel paclitaxel injection and a preparation method thereof. That is, an injection preparation is prepared by dissolving the paclitaxel with a solvent for injection and using a suitable stabilizer. The injection is diluted with 5%, 10% glucose or 0.9% sodium chloride solution into an injection solution, and has good stability and small side effects, ensuring the safety of the drug, and there is no appearance of precipitation after other dosage forms are diluted, further ensuring The effective use of paclitaxel.
  • the paclitaxel injection of the present invention is composed of the following components: w/v% content
  • the stabilizers include, but are not limited to, soybean phospholipid for injection, egg yolk phospholipid, Tween 80, cholesterol, sodium cholate, poloxamer 188 (F68) or glycerol monooleate, and one or more selected ones. mixture.
  • the solvent for injection includes, but is not limited to, anhydrous ethanol, glycerin, propylene glycol, polyethylene glycol and the like, and one or more kinds of mixtures are used.
  • the preparation method of the paclitaxel injection of the present invention is as follows:
  • the stabilizer into the solvent for injection according to the formula amount, dissolve the stabilizer at room temperature or with heating or ultrasonication, heat at 40-90 ° C, add paclitaxel, stir or ultrasonically dissolve paclitaxel completely, filter, dispense , disinfection, get paclitaxel injection.
  • the stabilizer is first dissolved in the solvent for injection, and then paclitaxel is added in order to avoid decomposition of paclitaxel by heat when the dissolution stabilizer is heated.
  • the filtering device in the preparation method includes, but is not limited to, a microporous membrane, a sand filter rod, a leaching funnel, a plate and frame filter press, and the like, and may be used alone or in combination of one or more.
  • the disinfection in the preparation method refers to sterilization including methods including, but not limited to, circulating steam, high pressure steam, etc., temperature 100-121 ° C, time 5 - 120 minutes.
  • the novel paclitaxel injection prepared by the invention is a colorless or light yellow transparent liquid.
  • the drug loading is 0.1-20 mg paclitaxel/ml.
  • the injection of the invention can be directly dissolved in 5%, 10% glucose or 0.9% sodium chloride solution into an injection solution.
  • the present invention provides a novel paclitaxel injection containing no polyoxyethylene castor oil, which has good stability and water solubility, and has a large drug loading amount, and can be directly dissolved in 5%, 10% glucose or 0.9% sodium chloride.
  • the solution is intravenously instilled after injection, which is convenient to use. After 72 hours, the content of the injection was 98% - 102% of the labeled amount, indicating that the stability was greatly improved.
  • no desensitization and strict monitoring are required before administration, which makes the patient easy to accept, improves the safety of clinical medication, and reduces the burden on the patient.
  • the injection also has a certain targeting effect.
  • the toxic side effects of the paclitaxel injection of the present invention are much lower than that of the paclitaxel cremophor preparation.
  • the paclitaxel injection of the invention overcomes a series of problems in the prior art various dosage forms in terms of encapsulation efficiency, stability, side effects, bioavailability and ease of administration, and is an ideal dosage form pursued by medical personnel and patients. .
  • the preparation method of the paclitaxel injection of the invention is simple and feasible, and is suitable for mass preparation and industrial production. detailed description
  • Example 7 A novel paclitaxel injection (injected with the formulation of Example 1) and a paclitaxel Crcmophor injection prepared with polyoxyethylene castor oil were apparently compared in a 5% glucose diluent, as shown in Table 1.
  • Example 8 Content stability test of novel paclitaxel injection in 5% glucose dilution (taking Example 1 injection as an example)
  • HPLC HPLC was used to determine the content of the new paclitaxel injection in 5% glucose dilution at different times. In order to avoid possible drug precipitation, the measurement results could not reflect the actual drug content. Therefore, when preparing the test solution, the test sample should be used first. After filtering the 0.22 um microporous membrane, it was then configured into a test solution. The result of this measurement is the true drug content. The test results are shown in Table 2.

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  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

L’invention concerne une injection de paclitaxel et sa méthode de préparation. Ladite injection de paclitaxel consiste en du paclitaxel 0,01-2 % (p/v) et du stabilisateur 1-70%(p/v), le reste étant du solvant pour injection, le stabilisateur étant un ou plusieurs agents sélectionnés à partir du phospholipide de graine de soja, du phospholipide de jaune d'oeuf, de Tween-80, du cholestérol, du cholate de sodium, de Poloxamer 188 et de la monooléine. Elle se prépare comme suit : dissoudre le stabilisateur dans ledit solvant par agitation thermique ou ultrasonique, ajouter le paclitaxel, agiter, filtrer, charger dans des contenants et stériliser. Elle a un faible effet secondaire toxique et est stable.
PCT/CN2006/001665 2005-07-20 2006-07-13 Injection de paclitaxel et sa méthode de préparation WO2007009355A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNA2005100279133A CN1723887A (zh) 2005-07-20 2005-07-20 一种紫杉醇注射剂及其制备方法
CN200510027913.3 2005-07-20

Publications (1)

Publication Number Publication Date
WO2007009355A1 true WO2007009355A1 (fr) 2007-01-25

Family

ID=35923602

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2006/001665 WO2007009355A1 (fr) 2005-07-20 2006-07-13 Injection de paclitaxel et sa méthode de préparation

Country Status (2)

Country Link
CN (1) CN1723887A (fr)
WO (1) WO2007009355A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019081285A1 (fr) 2017-10-27 2019-05-02 Basf Se Procédé de préparation d'éthylène-amines
WO2019081283A1 (fr) 2017-10-27 2019-05-02 Basf Se Procédé de préparation d'éthylèneamines
CN115634195A (zh) * 2022-10-26 2023-01-24 华北制药集团动物保健品有限责任公司 一种复方布他磷注射液的制备方法

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101190213B (zh) * 2006-11-30 2011-07-13 天津天士力集团有限公司 一种多西紫杉醇注射液及其制备方法
CN101190214B (zh) * 2007-01-31 2010-09-15 广东庆发药业有限公司 紫杉醇注射液及其制备方法
WO2008098415A1 (fr) * 2007-02-14 2008-08-21 Beijing Century Biocom Pharmaceutical Technology Co., Ltd. Composition pharmaceutique contenant du taxane et son procédé de préparation et d'application
CN101574318B (zh) * 2009-05-31 2011-06-15 海口市制药厂有限公司 一种紫杉醇注射液的制备方法
CN106880589B (zh) * 2017-03-07 2020-01-07 华北制药股份有限公司 一种紫杉醇注射液及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1421201A (zh) * 2002-12-16 2003-06-04 天津大学 紫杉烷类的注射药制剂
JP2005225818A (ja) * 2004-02-13 2005-08-25 Otsuka Pharmaceut Factory Inc パクリタキセル又はドセタキセルの医薬組成物
CN1714785A (zh) * 2004-06-28 2006-01-04 胡宇方 一种含有紫杉醇类化合物的浓缩乳化剂及其使用方法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1421201A (zh) * 2002-12-16 2003-06-04 天津大学 紫杉烷类的注射药制剂
JP2005225818A (ja) * 2004-02-13 2005-08-25 Otsuka Pharmaceut Factory Inc パクリタキセル又はドセタキセルの医薬組成物
CN1714785A (zh) * 2004-06-28 2006-01-04 胡宇方 一种含有紫杉醇类化合物的浓缩乳化剂及其使用方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JOURNAL OF SHENYANG PHARMACEUTICAL UNIVERSITY, vol. 21, no. 2, March 2004 (2004-03-01), pages 101 - 104, XP001249217 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019081285A1 (fr) 2017-10-27 2019-05-02 Basf Se Procédé de préparation d'éthylène-amines
WO2019081283A1 (fr) 2017-10-27 2019-05-02 Basf Se Procédé de préparation d'éthylèneamines
CN115634195A (zh) * 2022-10-26 2023-01-24 华北制药集团动物保健品有限责任公司 一种复方布他磷注射液的制备方法

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Publication number Publication date
CN1723887A (zh) 2006-01-25

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